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Background: Peripheral Nerve Stimulation (PNS) is an established therapy for chronic neuropathic pain of peripheral origin, typically following nerve injury. However, there is a paucity of Randomized Controlled Trials (RCTs) demonstrating the therapeutic benefits of PNS. The goals of the current study (COMFORT Study) are to document the safety and efficacy of the Nalu Neurostimulation in a PNS RCT, compared to conventional medical management (CMM). Methods/Design: This is a prospective, multicenter, RCT evaluating the treatment of neuropathic pain with PNS therapy. One of the following four regions will be targeted for treatment: low back, shoulder, knee or foot/ankle. Consented subjects will undergo a baseline evaluation, after which they are randomized 2:1 (PNS+CMM arm to CMM arm). Subjects randomized to PNS+CMM arm will undergo a trial implant period using best clinical practices. Subjects who pass the trial phase, by showing a ≥ 50% reduction in pain relative to baseline, will receive the permanent implant. All subjects receiving a permanent implant will be followed for a total of 36 months. At the 3-month primary end point, subjects in CMM arm will be given the option to crossover into PNS+CMM arm, beginning with a trial implant. The study duration is expected to be 5.5 years from first enrollment to last follow-up of last subject and subsequent study closure. Adverse events will be captured throughout the study. Discussion: The COMFORT study, described here, has the potential to demonstrate the efficacy and safety of the Nalu Neurostimulation System in the treatment of peripheral neuropathy. Results of this study will be the first Level-I evidence, out to 36 months, validating the use of this PNS system in the treatment of chronic pain. This study is designed to enroll the largest cohort, to date, of subjects comparing PNS+CMM vs CMM alone. Plain Language Summary: Peripheral nerve stimulation (PNS) has been used for decades to treat neuropathic pain of peripheral origin. This therapy typically involves the placement small (~1 mm diameter) cylindrical electrodes (leads) near the nerve(s) in question, which is then followed by the delivery mild electrical pulses to the target, thereby blocking the pain signal from reaching the central nervous system. Despite the clinical success of this approach, there are few randomized controlled trials (RCTs) demonstrating PNS efficacy in the treatment of peripheral neuralgia/neuropathy. This may be, in large part, due to a paucity of PNS devices that are small enough to deliver this therapy at multiple locations in the extremities and the torso. For example, most implantable pulse generators (IPGs) range in size from 14 to 40 cm3 in volume. The purpose of this RCT is to demonstrate the safety and efficacy of an externally powered micro-IPG (< 1.5 cm3 in volume), in the delivery of PNS to treat peripheral neuropathic pain. Active Arm subjects will receive therapy with the micro-IPG and continue to use conventional medical management (CMM); Control Arm subjects will be treated with CMM only. The primary endpoint is the responder rate at 3-months, in both arms, defined as the percentage of subjects with ≥ 50% pain reduction from baseline following implantation of the micro-IPG. Control Arm subjects will be given the option to crossover to the Active Arm at 3-months. Study subjects in both arms are followed out to 36 months. [ABSTRACT FROM AUTHOR]

Blood and lymphatic vessels in the body are central to molecular and cellular transport, tissue repair, and pathophysiology. Several approaches have been employed for engineering microfabricated blood and lymphatic vessels in vitro , yet traditionally these approaches require specialized equipment, facilities, and research training beyond the capabilities of many biomedical laboratories. Here we present xurography as an inexpensive, accessible, and versatile rapid prototyping technique for engineering cylindrical and lumenized microvessels. Using a benchtop xurographer, or a cutting plotter, we fabricated modular multi-layer poly(dimethylsiloxane) (PDMS)-based microphysiological systems (MPS) that house endothelial-lined microvessels approximately 260 μm in diameter embedded within a user-defined 3-D extracellular matrix (ECM). We validated the vascularized MPS (or vessel-on-a-chip) by quantifying changes in blood vessel permeability due to the pro-angiogenic chemokine CXCL12. Moreover, we demonstrated the reconfigurable versatility of this approach by engineering a total of four distinct vessel-ECM arrangements, which were obtained by only minor adjustments to a few steps of the fabrication process. Several of these arrangements, such as ones that incorporate close-ended vessel structures and spatially distinct ECM compartments along the same microvessel, have not been widely achieved with other microfabrication strategies. Therefore, we anticipate that our low-cost and easy-to-implement fabrication approach will facilitate broader adoption of MPS with customizable vascular architectures and ECM components while reducing the turnaround time required for iterative designs.

Background: Cancer-related bone pain remains a prevalent and frequently incapacitating ailment. Although conventional approaches effectively alleviate pain in most individuals, a subset of patients may continue to experience intractable pain. Current recommendations for treating cancer-related bone pain include oral analgesics and multimodal adjuvants, radiation therapy, and, in selected cases, intrathecal therapy. Cancer-related bone pain is mediated by a proliferation of sensory and sympathetic fibers. Thus, we believe that this pain can be successfully managed with minimally invasive sympathetic blockade (SB)., Methods: In a retrospective observational cohort, we reviewed patients who underwent single-shot SB for uncontrolled cancer-related bone pain despite receiving opiate analgesics and other interventions. We documented the Edmonton Symptom Assessment Scale (ESAS) ratings, the numeric rating scale (NRS) pain scores, and the morphine equivalent daily dose (MEDD) before and after SB., Results: The final cohort included 43 patients (median age, 58 years [range, 23-86 years]) with a history of bone pain experienced for a median of 6 months (IQR, 3-12 months). Comparing before and after the SB, patients had pain reduction -6 (IQR, -7 to -4; P<.001), reduction of ESAS scores of -17 (IQR, -23 to -3; P<.001), and reduction of MEDD -57 mg (95% CI, -79 to -34; P<.001). The treatment was well tolerated., Conclusions: Blockade of sympathetic afferent innervation is an effective and cost-effective modality that can be safely used to palliate intractable pain in patients with malignant bone pain.

Introduction: In adult patients with ureteropelvic junction obstruction (UPJO), little data exist on predicting pyeloplasty outcome, and there is no unified definition of pyeloplasty success. As such, defining pyeloplasty success retrospectively is particularly vulnerable to bias, allowing researchers to choose significant outcomes with the benefit of hindsight. To mitigate these biases, we performed an unsupervised machine learning cluster analysis on a dataset of 216 pyeloplasty patients between 2015 and 2023 from a multihospital system to identify the defining risk factors of patients that experience worse outcomes. Methods: A KPrototypes model was fitted with pre- and perioperative data and blinded to postoperative outcomes. T-test and chi-square tests were performed to look at significant differences of characteristics between clusters. SHapley Additive exPlanation values were calculated from a random forest classifier to determine the most predictive features of cluster membership. A logistic regression model identified which of the most predictive variables remained significant after adjusting for confounding effects. Results: Two distinct clusters were identified. One cluster (denoted as "high-risk") contained 111 (51.4%) patients and was identified by having more comorbidities, such as old age (62.7 vs 35.7), high body mass index (BMI) (26.9 vs 23.8), hypertension (66.7% vs 17.1%), and previous abdominal surgery (72.1% vs 37.1%) and was found to have worse outcomes, such as more frequent severe postoperative complications (7.2% vs 1.0%). After adjusting for confounding effects, the most predictive features of high-risk cluster membership were old age, low preoperative estimated glomerular filtration rate (eGFR), hypertension, greater BMI, previous abdominal surgery, and left-sided UPJO. Conclusions: Adult UPJO patients with older age, lower eGFR, hypertension, greater BMI, previous abdominal surgery, and left-sided UPJO naturally cluster into to a group that more commonly suffers from perioperative complications and worse outcomes. Preoperative counseling and perioperative management for patients with these risk factors may need to be thought of or approached differently.

Introduction: We investigated the risk of UTIs and complex UTIs associated with SGLT2 (sodium-glucose cotransporter-2) inhibitors in men, emphasizing older men at higher risk for voiding dysfunction., Methods: Utilizing a pharmacovigilance case-noncase design, we analyzed VigiBase reports from 1967 to 2022 among male patients. VigiBase is a comprehensive global database for drug safety. Disproportionality analysis, which compares the frequency of reported adverse events for specific drugs against other drugs, was conducted using reporting odds ratio (ROR) and empirical Bayes estimator (EBE). Age was stratified at 65 years as a threshold for increased susceptibility to male voiding dysfunctions. Sensitivity analyses were performed to compare SGLT2 inhibitor with other diabetes medications and years 2013 to 2022., Results: There were 484 UTIs (ROR 6.75 [95% CI: 6.17-7.39]; EBE 6.78) and 165 complex UTIs (ROR 8.09 [95% CI: 6.94-9.43]; EBE 8.60). In men under 65, there were 178 UTIs (ROR 6.82 [95% CI: 5.88-7.91]; EBE 6.99) and 65 complex UTIs (ROR 7.30 [95% CI: 5.71-9.32]; EBE 7.90). In men 65 and over, we found 153 UTIs (ROR 5.11 [95% CI: 4.35-5.99]; EBE 5.44) and 59 complex UTIs (ROR 8.79 [95% CI: 6.79-11.37]; EBE 9.60). Sensitivity analyses consistently showed significant signals., Conclusions: This study suggests an elevated risk for both UTIs and complex UTIs in men taking SGLT2 inhibitors, with a more pronounced risk for complex UTI in older men who may have benign prostatic hyperplasia-related voiding dysfunction. These findings highlight the need for a balanced approach in prescribing SGLT2 inhibitors, particularly in populations potentially more susceptible to UTIs.

Background: Neoantigen targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. At least 100 clinical trials involving these therapies are underway globally. Accurate identification and prioritization of neoantigens is highly relevant to designing these trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of massively parallel DNA and RNA sequencing technologies, it is now possible to computationally predict neoantigens based on patient-specific variant information. However, numerous factors must be considered when prioritizing neoantigens for use in personalized therapies. Complexities such as alternative transcript annotations, various binding, presentation and immunogenicity prediction algorithms, and variable peptide lengths/registers all potentially impact the neoantigen selection process. There has been a rapid development of computational tools that attempt to account for these complexities. While these tools generate numerous algorithmic predictions for neoantigen characterization, results from these pipelines are difficult to navigate and require extensive knowledge of the underlying tools for accurate interpretation. This often leads to over-simplification of pipeline outputs to make them tractable, for example limiting prediction to a single RNA isoform or only summarizing the top ranked of many possible peptide candidates. In addition to variant detection, gene expression and predicted peptide binding affinities, recent studies have also demonstrated the importance of mutation location, allele-specific anchor locations, and variation of T-cell response to long versus short peptides. Due to the intricate nature and number of salient neoantigen features, presenting all relevant information to facilitate candidate selection for downstream applications is a difficult challenge that current tools fail to address., Results: We have created pVACview, the first interactive tool designed to aid in the prioritization and selection of neoantigen candidates for personalized neoantigen therapies including cancer vaccines. pVACview has a user-friendly and intuitive interface where users can upload, explore, select and export their neoantigen candidates. The tool allows users to visualize candidates across three different levels, including variant, transcript and peptide information., Conclusions: pVACview will allow researchers to analyze and prioritize neoantigen candidates with greater efficiency and accuracy in basic and translational settings The application is available as part of the pVACtools pipeline at pvactools.org and as an online server at pvacview.org., Competing Interests: Conflict of Interest The authors declare that there is no conflict of interest.

Background: We report the results from the first large, postmarket, multicentre, randomised controlled trial (RCT) evaluating peripheral nerve stimulation (PNS) for the treatment of chronic peripheral pain with a micro-implantable pulse generator (micro-IPG)., Methods: Subjects meeting eligibility were randomised (2:1) to either the active arm receiving PNS and conventional medical management (CMM) or the control arm receiving CMM alone. Treatments were limited to the following areas: lower back, shoulder, knee and foot/ankle., Results: At 6 months, the active arm achieved an 88% responder rate with a 70% average reduction in pain. At the 3-month primary endpoint, the active arm achieved an 84% responder rate with an average pain reduction of 67% compared with the control arm, which achieved a 3% responder rate with an average pain reduction of 6%. Both responder rate and pain reduction in the active arm were significantly better than in the control arm (p<0.001). A majority of patient-reported outcomes also reached statistical significance. There have been no reports of pocket pain and no serious adverse device effects. 81% of subjects found the external wearable component of the PNS system to be comfortable., Conclusions: This study successfully reached its primary endpoint-the active arm achieved a statistically significant superior responder rate as compared with the control arm at 3 months. These RCT results demonstrated that PNS, with this micro-IPG, is efficacious and safe. This ongoing study will follow subjects for 3 years, the results of which will be reported as they become available., Competing Interests: Competing interests: GH is a consultant at Nalu Medical, Agitated Solutions, and a co-founder of Nesos. PS is a consultant for Nalu Medical, Saluda, SPR therapeutics and Medtronic. He is the Chief Medical Officer at electroCore. SK is an employee at Nalu Medical. JM is a consultant at Nalu Medical and owns stock in Nalu Medical. JH is a speaker and consultant for Nalu Medical. MJD consults for Avanos, Nalu, SPR Therapeutics; receives research support from Abbott, Avanos, Averitas, Mainstay, Nalu, Nature Cell, Saol, SPR Therapeutics and Vivex; and owns stock options in SPR Therapeutics, SynerFuse and Virdio., (© American Society of Regional Anesthesia & Pain Medicine 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

In most solid tumors, malignant cells coexist with non-cancerous host tissue comprised of a variety of extracellular matrix components and cell types, notably fibroblasts, immune cells, and endothelial cells. It is becoming increasingly evident that the non-cancerous host tissue, often referred to as the tumor stroma or the tumor microenvironment, wields tremendous influence in the proliferation, survival, and metastatic ability of cancer cells. The tumor stroma has an active biological role in the transmission of signals, such as growth factors and chemokines that activate oncogenic signaling pathways by autocrine and paracrine mechanisms. Moreover, the constituents of the stroma define the mechanical properties and the physical features of solid tumors, which influence cancer progression and response to therapy. Inspired by the emerging importance of tumor-stroma crosstalk and oncogenic physical forces, numerous biosensors, or advanced imaging and analysis techniques have been developed and applied to investigate complex and challenging questions in cancer research. These techniques facilitate measurements and biological readouts at scales ranging from subcellular to tissue-level with unprecedented level of spatial and temporal precision. Here we examine the application of biosensor technology for studying the complex and dynamic multiscale interactions of the tumor-host system., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cancer is a complex and dynamic disease that is aberrant both biologically and physically. There is growing appreciation that physical abnormalities with both cancer cells and their microenvironment that span multiple length scales are important drivers for cancer growth and metastasis. The scope of this review is to highlight the key advancements in micro- and nano-scale tools for delineating the cause and consequences of the aberrant physical properties of tumors. We focus our review on three important physical aspects of cancer: 1) solid mechanical properties, 2) fluid mechanical properties, and 3) mechanical alterations to cancer cells. Beyond posing physical barriers to the delivery of cancer therapeutics, these properties are also known to influence numerous biological processes, including cancer cell invasion and migration leading to metastasis, and response and resistance to therapy. We comment on how micro- and nanoscale tools have transformed our fundamental understanding of the physical dynamics of cancer progression and their potential for bridging towards future applications at the interface of oncology and physical sciences.